Neurologic disorders are becoming increasingly common. Thus, developing an effective treatment for neurologic disorders has become a high priority in the drug industry.
Neurologic disorders can generally be divided into two groups based on their physiological and pathological characteristics. Parkinson's disease, Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) are all progressive disorders (i.e., their symptoms are not apparent until months or more commonly years after the disease has begun), caused by an initial reduction of neuronal function, followed by a complete loss of function upon neuronal death. In addition, these progressive neurologic disorders are characterized by the presence of protein aggregates that are believed to hamper cellular functions (e.g., neurotransmission), and may ultimately result in cell death (Sasaki et al., Am. J. Pathol., 153:1149-1155 [1998]).
Multiple sclerosis is a disorder of the central nervous system, which is slowly progressive and is characterized by disseminated patches of demyelination in the brain and spinal cord, resulting in multiple and varied neurologic symptoms and signs, usually with remissions and exacerbations. The cause is unknown but an immunologic abnormality is suspected (THE MERCK MANUAL, 18th EDITION, 2009 MERCK & CO.). Several different drug therapies are currently being investigated.
While the aforementioned disorders are all slowly progressive, neurological dysfunction can also be caused by a more abrupt event such as an infarction of brain tissue, or stroke. Brain stroke is the third leading cause of death in the developed countries. Survivors often suffer from neurological and motor disabilities. The majority of central nervous system (“CNS”) strokes are regarded as localized tissue anemia following obstruction of arterial blood flow which causes oxygen and glucose deprivation. R(+)-N-propargyl-1-aminoindan has been shown to be an effective treatment for stroke and traumatic brain injury (See, e.g. U.S. Pat. No. 5,744,500).
A series of propargylamines, including Selegiline and Rasagiline, have been shown to prevent apoptosis in dopamine neurons in Parkinson's models (Naoi, M. et al. J. Neural Transmission (2002) 109: 607-721). N-Propargyl-1-Aminoindan has been shown to be useful for treating Parkinson's disease, dementia and depression (See, e.g. U.S. Pat. No. 5,453,446). The mechanism by which the propargylamines confer neuroprotection is not fully understood. However, it is clear that the mechanism involves a complex set of neurochemical events including alterations in Bcl-2, GAPDH, SOD and catalase (Youdim, M. B. H. Cell. Mol. Neurobiol. (2001) 21(6): 555-573).
However, additional agents to treat neurodegenerative diseases are needed.